Transplantation of a graft organ or tissue from a donor to a host patient is a feature of certain medical procedures and treatment protocols. Despite efforts to avoid graft rejection through host-donor tissue type matching, in transplantation procedures where a donor organ is introduced into a host, immunosuppressive therapy is generally required to the maintain viability of the donor organ in the host.
After an organ has been transplanted into the patient, the patient's immune system is suppressed to prevent rejection of the new organ. Despite the wide use of immunosuppressive therapy, organ transplant rejection can occur.
Organ transplant rejection comprises three separate categories: hyperacute, acute and chronic. Hyperacute rejection is characterized by rapid thrombotic occlusion of the graft vasculature within minutes to hours after organ transplantation. Hyperacute rejection is mediated in large part by pre-existing antibodies that bind to the epithelium and activate the complement cascade. Complement activation results in endothelial cell damage and subsequent exposure of the basement membrane, resulting in the activation of platelets, leading to thrombosis and vascular occlusion. As the field of transplantation has matured, hyperacute rejection has become less common due to blood antigen and MHC molecule matching between the donor organ and the recipient.
Acute rejection is sub-classified into acute vascular rejection and acute cellular rejection. Acute vascular rejection is characterized by necrosis of individual cells in the graft blood vessels. The process is similar to that of hyperacute rejection, but onset is often slower, within one week of rejection, and a T cell component may be involved. Acute vascular rejection is initiated by a response to alloantigens present on the vascular endothelial cells of the donor organ, resulting in the release of a cytokine cascade, inflammation, and eventual necrosis. Acute cellular rejection is often characterized by necrosis of the essential or parenchymal cells of the transplanted organ caused by the infiltration of host T lymphocytes and macrophages. The lymphocytes involved are usually cytotoxic T lymphocytes (CTL) and macrophages, both resulting in lysis of targeted cells. The CTLs are usually specific for graft alloantigens displayed in the context of MHC class I molecules.
Chronic rejection is the major cause of allograft loss and is characterized by fibrosis and loss of normal organ structures. Fibrosis may be the result of wound healing following the cellular necrosis of acute rejection, or may occur independently and without prior acute rejection. In addition, chronic rejection may lead to vascular occlusions thought to stem from a delayed type hypersensitivity response to alloantigens present on the transplanted organ. These alloantigens stimulate lymphocytes to secrete cytokines which attract macrophages and other effector cells eventually leading to an arteriosclerosis-like blockage.
In many cases, chronic graft injury or rejection (CR) is largely due to calcineurin-inhibitor drug nephrotoxicity (DT) and chronic allograft nephropathy (CAN), two conditions which may result in loss of graft function and early graft loss, premature to the life expectancy of the recipient. The incidence of chronic graft loss has remained unchanged over the last decade.
A biopsy is the only current gold standard for CAN and DT diagnosis. As both conditions are progressive post-transplantation, multiple graft protocol biopsies are required. However, the invasiveness of biopsy procedures is a limitation to this form of monitoring. In addition, variability of biopsy sampling and pathology analysis (2) adds a confounder to the differential diagnosis of these 2 conditions—the result of either too much drug (DT) vs. too little/inappropriate drugs (CAN)—with a common outcome of chronic fibrotic injury from differing mechanisms (non-immune vs. immune).
There is currently no method available to detect or to monitor future graft loss at the time of transplantation or acute rejection (AR) episodes. AR is a risk factor both for eventual graft loss, delayed recovery of graft function and even chronic rejection. Non-invasive monitoring methods for AR stratification, CR, DT and developing or established tolerance is currently not available, but would be very valuable, as the transplant biopsy, though the current gold standard, fails to stratify or prognosticate AR, differentiate CR clearly from DT or diagnose tolerance.
Accordingly, of interest would be the ability to evaluate likelihood of graft survival in a transplant recipient, e.g., following an AR episode, such that treatment protocols for transplant patients may be customized.